Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress

Abstract

The ability to respond to perturbations in endoplasmic reticulum (ER) function is a fundamentally important property of all cells, but ER stress can also lead to apoptosis. In settings of chronic ER stress, the associated apoptosis may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases, diabetes, atherosclerosis and renal disease. The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.

Figure 1

Prolonged activation of IRE1 may promote apoptosis. Studies with cultured cells have identified a pro-apoptotic IRE1–TRAF2–JNK pathway that can be activated by prolonged ER stress. Signal transduction between IRE1–TRAF2 and phosphorylation of JNK may be mediated in certain settings by the MAP kinase kinase kinase (MAPKKK) ASK1 and its activator, AIP1. JNK-induced apoptosis may involve the pro-apoptotic Bcl-2 family members, Bax and Bak, which in turn, can amplify the IRE1 signal. Prolonged IRE1-mediated activation of the RIDD pathway may promote apoptosis by degrading mRNAs encoding essential cell-survival proteins, including XPB1 itself.

Figure 2

Pathways through which prolonged activation of CHOP may promote apoptosis. Studies with both cultured cells and gene-targeted mouse models have identified a number of possible pro-apoptotic actions of prolonged CHOP expression, as depicted here and explained in detail in the text. Note that two of the major cell death pathways — the ERO1α–IP3R–Ca²⁺–CaMKII pathway and the Bcl-2 family member pathway — may lead to a common pro-apoptotic endpoint of outer mitochondrial membrane (OMM) permeabilization (dotted arrow; see text for details).

Figure 3

Examples of integration among the UPR apoptosis pathways. (a) In the simplest scenario, differential apoptotic signalling downstream of CHOP and IRE1 may lead to only partial cell death responses, and so the full apoptotic response may require activation of both pathways. (b) Both pathways can promote changes in Bcl-2 family protein expression or activity that favour cell death. (c) Both pathways can promote JNK activation, which when prolonged, can trigger cell death. Note that one of the mechanisms by which activated JNK leads to apoptosis is through Bax–Bak activation, possibly leading to further integration (purple dotted arrow). See text for details and for other possible areas of integration.

Figure 4

Examples of therapeutic strategies to prevent cell death in the setting of pathologic, prolonged ER stress. (a, b) Strategies directed towards IRE1- and CHOP-mediated apoptotic pathways, respectively. Note that several of the approaches are applicable to both (blue font). The common approaches include mitigation of ER stress itself by so-called proteostasis regulators and inhibition of JNK. See text for details.